Mutation of the hematopoietic cell phosphatase (Hcph) gene is associated with resistance to γ-irradiation-induced apoptosis in Src homology protein tyrosine phosphatase (SHP)-1-deficient "motheaten" mutant mice

Academic Article

Abstract

  • To determine the role of Src homology protein tyrosine phosphatase (SHP-1) in the ionizing radiation-induced stress response, we analyzed the apoptotic response and cell cycle function in irradiated spleen cells of motheaten (me/me) mice. The defect in me/me mice has been attributed to mutations of the Hcph gene, which encodes SHP-1. Homozygotes develop severe systemic autoimmune and inflammatory disease, whereas heterozygotes live longer and develop hematopoietic and lymphoid malignance. Spleen cells from C57BL/6 (B6)-me/me and B6-+/+ controls were analyzed after γ-irradiation from a 137Cs source. B6-me/me cells were significantly more resistant than B6-+/+ cells to γ-irradiation-induced apoptosis exhibiting a higher LD50. The defective apoptosis response of the B6-me/me cells was exhibited by T and B cells and macrophages. Of the Bcl-2 family members analyzed, a significant difference was observed in the transcription of Bax mRNA, which was up-regulated early after irradiation in B6-+/+ cells, but not B6-me/me cells. Analysis of 3,3′-dihexyloxacarbocyanine iodide revealed resistance to the γ-irradiation-induced mitochondrial transmembrane permeability transition in the B6-me/me cells. The blocking of the cell cycle in the G0/G1 phase characteristic of the irradiated B6-+/+ cells was not observed in the B6-me/me cells. There was decreased phosphorylation of p38 mitogen-activated protein kinase and increased phosphorylatlon of p53 from spleen cell lysates of irradiated B6-me/me mice compared with wild-type mice. These data suggest that SHP-1 plays an important role in regulation of apoptosis and cell cycle arrest after a γ-irradiation-induced stress response.
  • Published In

    Author List

  • Hsu HC; Shultz LD; Su X; Shi J; Yang PA; Relyea MJ; Zhang HG; Mountz JD
  • Start Page

  • 772
  • End Page

  • 780
  • Volume

  • 166
  • Issue

  • 2